ABSTRACT Cerebrovascular pathology is a very common comorbidity with Alzheimer's pathology. However, there is limited knowledge about the molecular mechanisms underlying the vascular contributions to cognitive impairment and dementia (VCID), the mechanisms that link VCID and Alzheimer progression, or how to intervene effectively in a complex multi-pathology environment. A key mechanism that drives pathophysiology progression in many CNS disorders is dysregulated neuroinflammatory responses from innate immune cells in the brain, and chronic neuroinflammation is a common feature seen early in both VCID and Alzheimer's disease (AD) progression. An important cell signaling pathway that contributes to neuroinflammatory responses in many CNS disorders is the p38 MAPK pathway, especially the p38? isoform. Activation of this important stress- regulated protein kinase occurs early in AD, p38? activation can lead to chronic neuroinflammation that has neurodegenerative consequences, and selective p38? inhibition is beneficial in AD animal models. However, there is no information on whether p38? is important in the detrimental inflammatory responses and subsequent neurodegenerative sequelae seen in VCID or comorbid VCID/AD pathology. We hypothesize that vascular dysfunction in the context of Alzheimer pathology creates an enhanced microglia inflammatory state, driven by p38? MAPK, that worsens the pathologic outcomes. We further postulate that the pathogenic events induced by comorbid VCID/AD will be modifiable by selective inhibition of p38?. To test our hypotheses, we will use the established hyperhomocysteinemia mouse model of cerebral small vessel disease to induce vascular injury in the APP/PS1 transgenic mouse. We will also use our recently developed, exceptionally specific, small molecule p38? inhibitor MW150, which is CNS-penetrant, safe, and efficacious in mouse models of AD pathology. The goal is to determine the therapeutic efficacy of MW150, in order to extend its potential for disease modification to a complex comorbid brain environment exhibiting both VCID and AD pathologies. Aim 1 will determine the minimum dose of MW150 that mitigates VCID-induced functional deficits in AD transgenic mice in a preventative treatment paradigm. Aim 2 will determine the mechanisms underlying MW150's actions in mitigating degenerative sequelae, by testing its effects on neuroinflammatory, vascular and synaptic dysfunction endpoints. Aim 3 will test MW150 in a therapeutic treatment paradigm, to determine efficacy in older mice when pathology is already present, mimicking what we see in the clinic with AD patients exhibiting comorbid vascular pathology. Because MW150 is a drug candidate in early stage clinical development, successful completion of these mechanistic and highly translational studies will extend the potential clinical utility of MW150 to a disease indication with complex comorbid pathologies. Given the urgent unmet medical need and MW150's unique potential, success will offer the potential for a new chemical entity and therapeutic intervention for VCID/AD, either as a mono-therapy or as part of a multi-drug armamentarium.